1. Field of the Invention
This invention relates to processes for the preparation of isoflavonoids, in particular haginin E, equol, daidzein, formononetin and the like, in which 7-benzyloxy-3-(4-methoxyphenyl)-2H-1-benzopyran is used as a common starting material.
2. Description of the Related Art
Isoflavonoids are one of the six main subclasses of flavonoids and the only one which contains a rearranged C15 skeleton based on 3-phenylchroman. The interesting biological properties described for isoflavonoids include antimicrobial, antioxidant, anti-inflammatory, phytoestrogenic and anti-cancer activities. Because isoflavonoids have diverse biological activities, they have attracted the attention of both nature product chemists and synthetic chemists.
Haginin E, equol, daidzein and formononetin are classified into the isoflavonoid family due to their chemical skeletons.

Haginin E (synonyms: dehydroequol; phenoxodiol; idronoxil; isoflav-3-ene-4′,7-diol; 7-hydroxy-3-(4-hydroxyphenyl)-2H-chromene) was first isolated from the stems of Lespedeza homoloba, and was initially found to have antioxidative activity against lipid peroxidation in the rat brain homogenate test. More recently, haginin E has been reported to induce apoptosis efficiently in epithelial ovarian carcinoma cells, but having little effect upon normal tissues. In addition, haginin E has been shown to inhibit proliferation in various human cancer cells in vitro and in vivo. Nowadays, haginin E has been subjected to Phase 3 clinical trials for the treatment of ovarian cancer. Nevertheless, the total synthesis of haginin E has received little attention, except for semi-syntheses from daidzein or formononetin.
Equol (synonyms: 4′,7-isoflavandiol; 4′,7-dihydroxyisoflavan; 7-hydroxy-3-(4-hydroxyphenyl)-2H-chroman) was first isolated from pregnant mares' urine in 1932 and was subsequently identified in the plasma of sheep (presumably derived from formononetin in red clover) and in human urine (from daidzein)(R. S. Muthyala et al. (2004), Bioorg. Med. Chem., 12:1559-1567). Equol is an isoflavandiol metabolized from daidzein by bacterial flora in the intestines, and it is a chiral molecule that can exist as the enantiomers R-equol and S-equol. Equol is known to have a high binding affinity to estrogen receptors, and causes direct inhibition of the growth of estrogen-dependent breast cancer. In addition, equol has been reported to have potential in anti-prostate cancer and cardiovascular disease therapies due to its bioactivities. Heretofore, only a few synthetic methods for racemic equol have been reported, including the hydrogenation of natural daidzein or formononetin (R. S. Muthyala et al. (2004), supra), and production via a Diels-Alder reaction between o-quinone methides and aryl substituted enol ethers (S. J. Gharpure et al. (2008), Tetrahedron Lett., 49:2974-2978). The racemic equol can be easily separated into (R)- and (S)-forms by chiral HPLC (R. S. Muthyala et at. (2004), supra). Other related chiral synthetic methods, including preparation via intramolecular Buchwald etherification to generate the chroman ring as the key intermediate (J. M. Heemstra et al. (2006), Org. Lett., 8:5441-5443), and synthesis from ethyl L-(−)-lactate via sequential reactions (Y. Takashima and Y. Kobayashi (2008), Tetrahedron Lett., 49:5156-5158), have been directed at (S-equol.
Daidzein (synonyms: 7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; 4′,7-dihydroxyisoflavone) and formononetin (synonyms: 7-hydroxy-4′-methoxy-isoflavone; 7-hydroxy-3-(4-methoxyphenyl)chromone; dadein 4′-methyl ether), both of which are found in different amounts in various legumes, such as soy, red clover, etc., have also attracted attention due to their diverse biological activities, such as estrogenic, anti-breast cancer, hormone replacement therapeutic and cancer chemoprevention activities. The methods for isolating daidzein and formononetin from plant materials have distinct drawbacks, including labor-intensive and time-consuming operations, as well as low yields. Most of the synthetic strategies towards daidzein and formononetin include acid-induced cyclization (Y. C. Chang et at (1994), J. Agric. Food Chem., 42:1869-1871; G. Y. Yeap et at. (2007), Liq. Cryst, 34:649-654; S. H. Jung et at. (2003), Eur. J. Med. Chem., 38: 537-545; H. Singh and R. Pratap (2006), Tetrahedron Lett., 47:8161-8163), Suzuki-Miyaura cross-coupling (F. X. Felpin et al. (2007), Tetrahedron, 63:3010-3016), biotransformation (M. Seeger et al. (2003), Appl. Environ. Micobio, 69:5045-5050; M. Luczkiewicz and A. Kokotkiewicz (2005), Plant Sci., 169:862-871; M. Miyazawa et al (2004), J. Mol. Catal B: Enzym., 27:91-95), and other methods.
WO 00/49009 A1 discloses a method for preparing an isoflavan-4-ol of the following formula (II):

the process comprising hydrogenating an isoflavone of the following formula (I):
                wherein in formulae (I) and (II), R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen, hydroxy; OR9, OC(O)R9, OS(O)R9, alkyl, haloalkyl, aryl, arylalkyl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo; and R9 is alkyl, haloalkyl, aryl, arylalkyl or alkylaryl.        
According to WO 00/49009 A1, the resultant isoflavan-4-ol of formula (II) may be further dehydrated and optionally deprotected or transformed so as to obtain an isoflav-3-ene of the following formula (III):

wherein R1, R2, R3, R4, R5, R6, R7 and R8 are the same as those defined above for formulae (I) and (II).
However, it is noted that the preparation method as disclosed in WO 00/49009 A1 is time-consuming and gives an unsatisfactory yield in the production of haginin E (see Examples 1, 13, 25 and 37 exemplified in the Specification of WO 00/49009 A1).
WO 00/49009 A1 further discloses that the isoflav-3-ene of formula (III) may be hydrogenated to give an isoflavan of the following formula (V):

wherein R1, R2, R3, R4, R5, R6, R7 and R8 are the same as those defined above for formulae (I) and (II).
However, it is noted that the preparation method as disclosed in WO 00/49009 A1 is time-consuming and gives an unsatisfactory yield in the production of equol (see Examples 1, 13, 25, 57 and 59 exemplified in the Specification of WO 00/49009 A1).
WO 2005/103025 A1 discloses a method for preparing a hydroxy-substituted isoflav-3-ene, comprising the steps of hydrogenating a hydroxy-substituted isoflavone in the presence of a basified catalyst to prepare a hydroxy-substituted isoflavan-4-ol, and dehydrating the hydroxy-substituted isoflavan-4-ol. The Examples provided in the Specification of WO 2005/103025 A1 only demonstrate the synthesis of haginin E starting from daidzein. Although it is stated in the Specification of WO 2005/103025 A1 that when the method as disclosed was scaled up, the obtained yield could reach 60-65% and greater, there is no indication of the actual yield as obtained from the Examples exemplified therein.
US 2007/0027329 A1 discloses the synthesis of (S)-equol (see Examples 1-6) and (R)-equol (see Examples 1-4 and 7-8), which starts from daidzein and involves a series of reactions, including end group protection, hydrogenation, reduction, dehydration, enantioselective hydrogenation, and end group deprotection. According to US 2007/0027329 A1, an Ir catalyst having a chiral ligand should be used in the enantioselective hydrogenation. In addition, referring to Example 10 exemplified in the Specification of US 2007/0027329 A1, the intermediate compound as obtained in Example 4 could be deprotected to give haginin E (see Examples 1-4 and 10).
US 2007/0149788 A1 discloses an improved method for preparing (+/−)-equol, comprising reducing an organic diester of daidzein under hydrogen-transfer conditions using palladium hydroxide catalyst.
In spite of the fact that several methods for the synthesis of haginin E, equol, daidzein and formononetin have been reported, some disadvantages still exist, including tedious reaction conditions, low yields and multistep sequences. In addition, the lack of diversity for preparing these compounds is also a shortcoming. Therefore, it is highly desired to develop new preparation processes for these bioactive compounds that are time- and cost-saving while affording a high yield.
Through a thorough analysis of the chemical skeletons of haginin E, equol, daidzein and formononetin, the applicants endeavored to explore a compound that was easy to obtain and could be used as a common starting material for the synthesis of these four bioactive compounds, as well as their analogues. The applicants surprisingly found from retro-synthetic analysis that 7-benzyloxy-3-(4-methoxyphenyl)-2H-1-benzopyran was a perfect candidate for this goal. Based on this finding, the applicants developed new approaches that are simple and efficient in the synthesis of isoflavonoids, in particular haginin E, equol, daidzein, formononetin and the like, while affording a satisfactorily high yield.